Amyloid Oligomers of Mutant p53 in Living Cells Result in Oncogenic Gain of Function in Glioblastoma
61 Pages Posted: 5 Sep 2019 Sneak Peek Status: PublishedMore...
Tumor-associated p53 mutations endow cells with malignant phenotypes, including chemoresistance to standard treatments. Amyloid-like oligomeric species of mutant p53 have been attributed to transformation of the p53 tumor suppressor into an oncogene. However, the composition and distribution of mutant p53 oligomers linked to a chemoresistance phenotype are unknown. Knowledge of the mechanism involved in the conversion of p53 is also sparse. Here, we report the massive accumulation of a p53 mutant within amyloid-like p53 oligomers in brain cells from glioblastoma tumors leading into chemoresistance gain of function. This finding, along with statistical analysis of data from fluorescence fluctuation spectroscopy, pressure-induced measurements, and thioflavin T kinetics, demonstrates the distribution of oligomers larger than the active tetrameric form of p53 in the nuclei of living cells and the destabilization of native-drifted p53 species that become amyloid. Collectively, these results suggest the role of amyloid-like mutant p53 oligomers as participants in the chemoresistance phenotype of malignant and invasive brain tumors and shed light on new therapeutic options to avert cancer.
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